The present invention relates to compositions and methods for the treatment and diagnosis of urinary calculi. In particular, it relates to the treatment and diagnosis using compositions comprising quadrivalent metal ions and bisphosphonates.
Urinary stones or calculi usually arise because of the breakdown of the balance between the need for kidneys to conserve water and at the same time excrete materials that have low solubility. Although urine contains substances that inhibit crystallization, calcium salts (calcium oxalate or calcium phosphate), uric acid, cystine, and struvite in urine can form crystals which grow and aggregate to form stones. As the stones grow on renal papillae or within the collecting system, they typically do not produce symptoms. The stones may, however, break loose and enter the ureter or occlude the ureteropelvic junction, causing pain and obstruction.
One of the problems facing the physician caring for patients with urinary stone disease is lack of compliance with medical treatment. It is estimated that only 40-60% of patients comply with long-term medical therapies in general. Less frequent dosing intervals are associated with better compliance. Except for twice daily administration for thiazides, medical regimens for calcium urolithiasis usually require 3 to 4 times daily dosing. It can be difficult to convince the average young healthy patient with calcium urolithiasis, who may be asymptomatic between episodes of colic, to remain on one of these medical regimens.
Current medical therapies prevent calcium stone formation by one of two general mechanisms: 1) reduction of the solute concentrations that are the driving physiochemical force for stone formation, either by decreasing the absolute concentration of mineral species (increased fluid intake, cellulose phosphate, orthophosphates, and thiazides) or by complexing active species in the urine (citrate and magnesium); and 2) competition for, or poisoning of, active growth sites on the calculi surface (magnesium, citrate, and orthophosphates). Agents acting through the former mechanism need to be present during any periods of relative supersaturation in order to be effective, which generally requires frequent dosing. Agents inhibiting growth at the calculi surface may or may not need to be present in the urine at all times.
It has been demonstrated that aggregation and growth of both calcium oxalate and calcium phosphate crystals are slowed by bisphosphonates. In particular, etidronate (EHDP), the first bisphosphonate marketed for therapeutic use, was found to reduce calcium oxalate crystalluria in stone-formers (Robertson et al. Clin. Sci. Mol. Med. 47:13 (1974)). Subsequent human trials to inhibit calculi formation were disappointing, however, because of incomplete resolution of stone activity and/or excessive musculo-skeletal side-effects. It was thought that since the high doses of EHDP required to constantly inhibit urine crystallization apparently had adverse bone effects, oral EHDP therapy was not promising for urolithiasis. Reports of research efforts with bisphosphonates towards urolithiasis have been rare since 1979.
The prior art thus lacks effective methods of calculi prophylaxis that do not require intensive medical therapy. In particular, inhibitors which bind calculi with great affinity and are not degraded, are particularly desirable because frequent dosing should not be necessary. Such an agent would be very useful clinically, not only for diagnosis and prophylaxis in recurrent stone-formers but also for suppressive therapy in patients with small fragments remaining after lithotripsy. The present invention addresses these and other needs.